Project Summary The long-term objective of my research program is to understand the molecular genetic mechanisms and driving forces of phenotypic variation and evolution, where the phenotype may be at molecular, cellular, tissue, organ, organismal or other levels. Gene expression is a phenotypic trait at the molecular level that is critical to all forms of life. This proposal centers on one aspect of gene expression known as position effect, which refers to the influence of the chromosomal location of a gene on its activity. Position effect has been implicated in a number of genetic diseases such as sex reversal, aniridia (absence of iris), and holoprosencephaly (a brain developmental disorder that typically leads to embryonic death). Any genetic disease caused by a chromosomal rearrangement that does not disrupt gene structure may be regarded as a result of position effect. Position effect has been observed many times in transgenic organisms, revealing the significance of the location at which the transgene is placed in a genome on its expression. Position effect has also been invoked in the explanations of multiple nonrandom features of genome organization. Despite its importance, our knowledge about the pattern and mechanism of position effect is limited and many hypotheses regarding position effect remain untested. Past studies of position effect focused on the role of heterochromatin, largely ignoring euchromatin where the vast majority of genes are located (and translocated in mutants and in evolution). A genomic study of position effects on mean protein expression and expression noise in the budding yeast Saccharomyces cerevisiae is proposed. The generated data will be used to probe the general patterns of position effects, to study the underlying genetic and epigenetic mechanisms of position effects, and to test the role of position effects in the formation of nonrandom features of genome organization. Furthermore, a series of manipulative experiments will be conducted in yeast to test a previously unrecognized role of position effect on expression noise in the origin of chromosomal clustering of functionally related genes. Overall, this project is expected to (i) provide unprecedented genome-wide information of position effect on gene expression and expression noise in yeast, (ii) uncover the molecular and mechanistic basis of position effects, and (iii) deepen our understanding of the role of position effect in the evolution of eukaryotic genome organization.